WO2011108425A1 - Méthode de préparation d'un immunomodulateur et immunomodulateur - Google Patents

Méthode de préparation d'un immunomodulateur et immunomodulateur Download PDF

Info

Publication number
WO2011108425A1
WO2011108425A1 PCT/JP2011/054072 JP2011054072W WO2011108425A1 WO 2011108425 A1 WO2011108425 A1 WO 2011108425A1 JP 2011054072 W JP2011054072 W JP 2011054072W WO 2011108425 A1 WO2011108425 A1 WO 2011108425A1
Authority
WO
WIPO (PCT)
Prior art keywords
lactic acid
immunomodulator
surfactant
extract
cells
Prior art date
Application number
PCT/JP2011/054072
Other languages
English (en)
Japanese (ja)
Inventor
裕樹 勘里
るみ子 桑名
茂 藤原
泰生 隅田
雅仁 橋本
Original Assignee
カルピス株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by カルピス株式会社 filed Critical カルピス株式会社
Publication of WO2011108425A1 publication Critical patent/WO2011108425A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a method for producing an immunomodulator using lactic acid bacteria as a raw material and having an activity of inducing production of cytokines such as IL-10 and IL-12 involved in immune reaction, and an immunomodulator obtained by the method.
  • Lactic acid bacteria are highly safe among microorganisms as typical probiotics, and are applied to food-related industries such as fermented foods. Lactic acid bacteria are known to exhibit immunoregulatory effects such as intestinal regulation and antiallergy by being taken into the body in the form of fermented milk.
  • Patent Document 1 discloses that Lactobacillus acidophilus strain L-92 has an antiallergic action.
  • Patent Document 2 discloses that microorganisms including lactic acid bacteria have IL-10 production-inducing activity and IL-12 production maintenance or suppression action.
  • Patent Document 3 proposes that a component obtained by extracting a cell wall component of Lactobacillus acidophilus complex with a surfactant or the like has a pathogen infection protective action.
  • inflammation is mentioned as the main symptom of autoimmune diseases such as inflammatory bowel disease. Inflammation is thought to be caused by the balance between the cytokine that gives it and the cytokine receptor (receptor) that receives the command. In such inflammation, the balance of cytokine production is greatly involved in the development of autoimmune diseases, and the development of active ingredients that can regulate the production of these cytokines is considered important for the prevention and treatment of diseases.
  • IL-10 is known to mainly promote the proliferation of B cells and differentiation into antibody-secreting cells, and in most cases, is known to exhibit anti-inflammatory activity. IL-10 is considered to be a regulator of connective tissue destruction seen in chronic inflammatory diseases.
  • IL-12 is a cytokine produced early in the inflammatory cascade mainly by antigen-presenting cells such as macrophages, and is regarded as an important cytokine for the production of a Th1 immune response. That is, IL-12 is generally known to exhibit cellular immunity enhancing activity. In immunomodulators, these components having a regulatory action on IL-10 and IL-12 are particularly effective, and development of a production method that can be obtained as a component that can be easily added to pharmaceuticals, foods, etc. is desired.
  • the present inventors have found that a component obtained by shaking and extracting lactic acid bacterial cells with a surfactant, particularly a highly fat-soluble fraction centering on the cell membrane of the bacterial cells,
  • the present invention was completed by confirming the existence of an active component of an immunomodulator having cytokine-inducing activity such as -10 and / or IL-12.
  • an immunomodulator comprising a step of shaking a mixture of lactic acid bacteria and a surfactant solution, and a step of separating and recovering an extract from the obtained shake product.
  • a method is provided.
  • the step of disrupting the lactic acid bacteria cells, the step of shaking the mixture of the disrupted lactic acid bacteria cells and the surfactant solution, and the step of separating and recovering the extract from the obtained shake product A method for producing an immunomodulator is provided.
  • a step of disrupting lactic acid bacteria a step of concentrating the disrupted bacteria to obtain a fraction containing at least a cell membrane component of the disrupted bacteria, and the resulting concentrate and interface
  • a method for producing an immunomodulating agent comprising a step of shaking a mixture with an active agent solution, and a step of separating and recovering an extract from the obtained shaking product.
  • an immunomodulator obtained by the above production method particularly an immunomodulator having IL-12 and / or IL-10 production inducing activity.
  • the method for producing an immunomodulator of the present invention comprises a step of shaking a lactic acid bacterium cell, a crushed lactic acid bacterium cell or a mixture of the concentrate and a surfactant solution, and separating and recovering an extract from the obtained shaked material. Therefore, it is possible to easily obtain an immunomodulator that is excellent in immunomodulatory action, in particular, excellent in production-inducing activity of cytokines such as IL-10 and / or IL-12. Since the obtained immunomodulator can easily separate water-insoluble cell walls and the like, it has an effect that it can be easily used as a pharmaceutical or a food additive. In particular, since it has an excellent effect on the production induction activity of cytokines such as IL-10 and / or IL-12, it is particularly useful for immunoregulation such as anti-inflammatory properties.
  • FIG. 4 is a graph showing IL-12 production inducing ability of the extract obtained by each surfactant measured in Example 2.
  • FIG. 4 is a graph showing the IL-10 production inducing ability of the Triton X114 extract measured in Example 3. It is a graph which shows the IL-12 production inducibility of 1% SDS extract and 2% Triton X-114 extract which were measured in Example 4. It is a graph which shows the IL-12 production induction ability of each fraction which fractionated 2% Triton X-114 extract measured in Example 5 by HPLC.
  • the production method of the present invention comprises a step of shaking a mixture of lactic acid bacteria cells and a surfactant solution, and a step of crushing lactic acid bacteria cells, and then a mixture of the crushed lactic acid bacteria cells and a surfactant solution.
  • a step of shaking or a step of crushing lactic acid bacteria is performed.
  • Thereafter, in order to obtain a fraction containing at least cell membrane components of the disrupted cells, at least a step of concentrating the disrupted cells and a step of shaking the mixture of the obtained concentrate and the surfactant solution are performed.
  • the lactic acid bacteria used in the present invention can target many lactic acid bacteria conventionally known to have an immunomodulating action.
  • Specific examples include Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus plantarum, Lactobacillus gasseri, Lactobacillus johnsonii, Lactobacillus helveticus, Lactobacillus delbruecki. It is not limited.
  • Lactobacillus acidophilus CL0062 strain (patent biological deposit center deposit number FERM BP-4980), Lactobacillus acidophilus CL-92 strain (patent biological deposit center deposit number FERM BP-4981), Lactobacillus fermentum CP-34 A strain (patent biological deposit center deposit number FERMFBP-8383) is preferably mentioned.
  • Any medium can be used as the medium for culturing lactic acid bacteria as long as the lactic acid bacteria can grow.
  • Animal milk, skim milk, milk whey, MRS medium, GAM medium, BL medium, Briggs Liver Broth Or a synthetic medium can be used.
  • the culture temperature can be 25 ° C to 50 ° C, preferably 35 ° C to 42 ° C.
  • the culture time can be 3 to 48 hours, preferably 8 to 30 hours.
  • Lactic acid bacteria can be collected by, for example, collecting cells from the culture medium after completion of culture by centrifugation, filtration, etc. to make only the cells, freeze-dried cells, and heat-treated cells. be able to.
  • the step of crushing lactic acid bacteria can be carried out by a known crushing step such as a physical crushing step using glass beads or the like, or an ultrasonic crushing step.
  • the crushing conditions can be selected as appropriate so that the cell membrane of lactic acid bacteria can be easily separated.
  • the step of concentrating the disrupted cells includes, for example, centrifuging the disrupted cells at about 0 ° C. to room temperature. The supernatant can be collected by a method such as removing unbroken cells.
  • the step of shaking the lactic acid bacteria cells, the crushed lactic acid bacteria cells, and the mixture of the concentrate and the surfactant solution is, for example, at about 0 to 37 ° C., using a stirring / shaking machine. For 1 to 24 hours by stirring and shaking.
  • the surfactant used in the shaking can include, for example, a nonionic surfactant, an amphoteric surfactant, or an anionic surfactant, and more specifically, for example, octyl glucoside, CHAPS, Mention may be made of sodium dodecyl sulfate, polyoxylen sorbitan monolaurate (Tween 20), polyoxylen sorbitan monooleate (Tween 80) or Triton X114.
  • the concentration of the surfactant is not particularly limited, but a concentration of 0.1 to 5% by mass / L is preferable because it is advantageous for extraction of active ingredients.
  • a solvent for the surfactant solution water is usually used, but a phosphate buffer solution, methanol, ethanol, or a mixed solvent of these with water can be used.
  • the step of separating and recovering the extract from the obtained shake product can be performed, for example, by centrifugation, and further purified, concentrated, and dried by a commonly used method such as column chromatography. It can also be frozen. At this time, in order to recover the used surfactant, it is preferable to recover the surfactant while replacing it with water using an ultrafiltration membrane or the like.
  • the extract to be separated and recovered preferably contains a highly lipophilic fraction containing a large amount of active ingredients having an immunomodulating action.
  • the fraction particularly preferably includes a fraction eluted in isopropanol having a concentration of 50 to 85% by mass.
  • the immunomodulator obtained by the production method of the present invention can be used, for example, in the form of solid agents such as tablets, granules, powders, capsules, solutions such as solutions, suspensions, emulsions, freeze-dried agents, etc.
  • it can be used as various food additives.
  • These preparations can be made by a method of appropriately adding conventional additives such as known stabilizers, wetting agents, emulsifiers, binders, tonicity agents, excipients and the like.
  • autoimmune disease inflammatory bowel disease
  • allergy psoriasis
  • rejection at the time of organ transplantation, virus infection, tumor, etc.
  • the immunomodulator of the present invention can be used as a food or drink useful for improvement, prevention, etc.
  • an active ingredient having an immunomodulatory action is contained in a highly lipophilic fraction, by separating and purifying such a fraction, the cell wall of lactic acid bacteria cells is obtained.
  • a component from which a water-precipitating substance such as the above has been removed can be used as an active ingredient.
  • the active ingredient from which such a water-precipitating substance has been removed is a commercial value that does not cause precipitation, particularly when added to transparent beverages such as teas, waters, alcoholic beverages, and dissolved or emulsified with an emulsifier. High beverage.
  • the administration method of the immunomodulator of the present invention is not particularly limited, but oral administration and intravenous injection are preferable.
  • the dose is preferably determined individually in consideration of the age, weight, etc. of the administration subject.
  • it can be 0.00001 g / day or more, preferably 0.001 g / day as a dry product of the extracted extract, and can be administered once a day, or multiple times It can also be distributed.
  • Example 1 Preparation of bacterial cells Lactobacillus acidophilus L-92 strain is cultured at 37 ° C for 18-30 hours, collected by centrifugation, washed, freeze-dried, and L-92 bacterial cells are obtained. Obtained. Preparation of Extract To 10 mg of L-92 cells, 1 ml of various surfactant solutions having the concentrations shown in Table 1 was added, and the mixture was gently shaken at 4 ° C. overnight.
  • the supernatant was collected by centrifugation at 10,000 rpm for 10 minutes, the surfactant was removed from the supernatant by using an ultrafiltration membrane (MWCO 3,000, manufactured by Millipore), and water was added. By repeating this operation, the surfactant was removed as much as possible.
  • the solution was added in an amount of 1/25 per ml of cell culture medium and allowed to act on mouse peritoneal macrophages. The amount of IL-12 in the culture supernatant after culturing for 24 hours was measured by ELISA.
  • IL-12 Inducing Activity Measurement Method Thioglycolate medium (DIFCO) was intraperitoneally administered to female BALB / c mice, and the mice were sacrificed 3-4 days later.
  • Peritoneal cells (PEC) were obtained by injecting 5 ml of PBS into the peritoneal cavity and collecting it. 2 ⁇ 10 5 peritoneal cells were seeded in a 96-well plate and cultured for 1 hour.
  • RPMI medium containing 10% FBS and 1% penicillin / streptomycin solution (GIBCO, Cat. No. 15140) was used. The culture solution was removed, a culture solution containing 10 ng / ml IFN- ⁇ was added, and the culture was performed overnight.
  • the culture solution which diluted the sample was added there, and it culture
  • the amount of IL-12 produced in the culture supernatant was measured by ELISA using OptEIA TM Mouse IL-12 p70 ELISA Set (BD Biosciences Cat 555256). The results are shown in Table 1.
  • Example 2 Preparation of extract 8 ml of PBS was added to 800 mg of L-92 cells, the same volume of glass beads was added, and the cells were disrupted by vigorous shaking. The supernatant was collected by centrifugation at 3500 rpm for 15 minutes at 4 ° C. to remove unbroken cells and glass beads. This supernatant was suspended in a precipitate (membrane fraction) centrifuged at 33000 ⁇ g for 90 minutes at 4 ° C. by adding 10 ml of PBS, and 200 ⁇ l of Tween 20 or Tween 80 or Triton X 114 was added. Shake at 4 ° C. for 1 hour. Centrifuge at 8000 rpm.
  • Triton X 114 the lower layer (Triton X 114 layer) is recovered, methanol is added to precipitate the extract, and the precipitate is suspended in a 1% octyl glucoside solution to obtain Triton X 114 extract. did.
  • Example 3 Preparation of Extract Triton X114 extract was prepared in the same manner as in Example 2.
  • Cell Culture Thioglycolate medium DIFCO
  • DIFCO Cell Culture Thioglycolate medium
  • PEC Peritoneal cells
  • 2 ⁇ 10 5 peritoneal cells were seeded in a 96-well plate and cultured for 1 hour.
  • RPMI medium containing 10% FBS and 1% penicillin / streptomycin solution (GIBCO, Cat. No. 15140) was used. The culture solution which diluted the sample was added there, and it culture
  • the amount of IL-10 produced in the culture supernatant was measured by ELISA using OptEIA TM Mouse IL-10 ELISA Set (BD Biosciences). The results are shown in FIG. From the results shown in FIG. 2, the extract extracted from lactic acid bacteria using a surfactant also showed a remarkable inducing activity of IL-10, an anti-inflammatory cytokine.
  • Example 4 Preparation of extract As the extract, 1% SDS extract prepared in Example 1 and 1% Triton X-114 extract prepared in Example 2 were used. I investigated. Cell culture was performed in the same manner as in Example 1. The results are shown in FIG. From the results of FIG. 3, it was found that the ability to induce IL-12 production increases by adding a step of physically disrupting the cells and concentrating the membrane fraction. From this, it was found that by concentrating the cell membrane fraction of bacterial cells, the active ingredient was concentrated and a more excellent effect was obtained.
  • the dried fraction fraction was suspended in a 1% octyl glucoside solution and examined for IL-12 production inducing ability.
  • Cell culture was performed in the same manner as in Example 1. The results are shown in FIG. From the results shown in FIG. 4, it was found that fractions 6 to 8 having a high fat solubility eluted in isopropanol having a concentration of about 50 to 85% by mass contained an active ingredient showing IL-12 production inducing ability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

La présente invention concerne une méthode d'obtention aisée d'un immunomodulateur, ladite méthode employant des cellules de lactobacille au titre de produit de départ et permettant d'obtenir un principe actif d'activité immunomodulatrice de façon simple et, de plus, d'une forme facilement incluse dans les médicaments et les aliments fonctionnels. La présente invention concerne également un immunomodulateur obtenu par le biais de ladite méthode. La méthode de préparation implique une étape d'agitation d'un mélange de cellules de lactobacille et d'une solution de tensioactifs et une étape de séparation et de récupération d'un extrait à partir du mélange agité ; et la méthode implique particulièrement une étape d'écrasement des cellules de lactobacille, une étape de concentration des cellules bactériennes écrasées pour obtenir une fraction comprenant au moins les composants de la membrane cellulaire des cellules bactériennes écrasées, une étape d'agitation du mélange du concentré obtenu et de la solution de tensioactif, et une étape de séparation et de récupération d'un extrait à partir du mélange agité obtenu.
PCT/JP2011/054072 2010-03-04 2011-02-24 Méthode de préparation d'un immunomodulateur et immunomodulateur WO2011108425A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2010048433 2010-03-04
JP2010-048433 2010-03-04

Publications (1)

Publication Number Publication Date
WO2011108425A1 true WO2011108425A1 (fr) 2011-09-09

Family

ID=44542079

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2011/054072 WO2011108425A1 (fr) 2010-03-04 2011-02-24 Méthode de préparation d'un immunomodulateur et immunomodulateur

Country Status (2)

Country Link
TW (1) TW201143786A (fr)
WO (1) WO2011108425A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019210242A (ja) * 2018-06-04 2019-12-12 雪印メグミルク株式会社 ラクトバチルス属の乳酸菌を有効成分とするｓｒｃａｐ発現抑制用組成物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05201828A (ja) * 1991-10-22 1993-08-10 Pacific Chem Ind Co 化粧料用乳酸菌製剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05201828A (ja) * 1991-10-22 1993-08-10 Pacific Chem Ind Co 化粧料用乳酸菌製剤

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
AKIKO TORII ET AL.: "Lactobacillus Acidophilus Strain L-92 Regulates the Production of Th1 Cytokine as well as Th2 Cytokines", ALLERGOLOGY INTERNATIONAL, vol. 56, 2007, pages 293 - 301, XP008120132, DOI: doi:10.2332/allergolint.O-06-459 *
LAIN C. SUTCLIFFE ET AL.: "Extraction of lipoteichoic acid from Streptococcus mutans with the non-ionic detergent Triton X-114", JOURNAL OF MICROBIOLOGICAL METHODS, vol. 17, 1993, pages 215 - 225 *
LOUISE HJERRILD ZEUTHEN ET AL.: "Toll-like receptor 2 and nucleotide-binding oligomerization domain-2 play divergent roles in the recognition of gut-derived lactobacilli and bifidobacteria in dendritic cells", IMMUNOLOGY, vol. 124, 2008, pages 489 - 502 *
MASAHITO HASHIMOTO ET AL.: "Lipoprotein is a predominant Toll-like receptor 2 ligand in Staphylococcus aureus cell wall components", INTERNATIONAL IMMUNOLOGY, vol. 18, no. 2, 2005, pages 355 - 362 *
MASAHITO HASHIMOTO ET AL.: "Not Lipoteichoic Acid but Lipoproteins Appear to Be the Dominant Immunobiologically Active Compounds in Staphylococcus aureus", THE JOURNAL OF IMMUNOLOGY, vol. 177, 2006, pages 3162 - 3169 *
RUMIKO KUWANA: "An antiallergic effect of Lactobacillus acidophilus L-92 strain", THE FOOD INDUSTRY, vol. 53, no. 6, 28 February 2010 (2010-02-28), pages 35 - 42 *
TETSUYA MATSUGUCHI ET AL.: "Lipoteichoic Acids from Lactobacillus Strains Elicit Strong Tumor Necrosis Factor Alpha-Incucing Activities in Macrophages through Toll-Like Receptor 2", CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY, vol. 10, no. 2, 2003, pages 259 - 266 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019210242A (ja) * 2018-06-04 2019-12-12 雪印メグミルク株式会社 ラクトバチルス属の乳酸菌を有効成分とするｓｒｃａｐ発現抑制用組成物
JP7224114B2 (ja) 2018-06-04 2023-02-17 雪印メグミルク株式会社 ラクトバチルス属の乳酸菌を有効成分とするｓｒｃａｐ発現抑制用組成物

Also Published As

Publication number Publication date
TW201143786A (en) 2011-12-16

Similar Documents

Publication Publication Date Title
WO2018004145A1 (fr) Composition anti-inflammatoire contenant une vésicule extracellulaire dérivée d'une levure
JP2007070249A (ja) 免疫機能調節剤、抗アレルギー剤、免疫調節用組成物及び抗アレルギー用組成物並びにこれらが含まれた食品
KR101971546B1 (ko) 유산균, 노루궁뎅이버섯 추출물 및 은행잎 추출물을 포함하는 인지기능 또는 기억능력 개선용 식품 조성물
CA3086031C (fr) Composition pour la dermite de contact
JPWO2019087280A1 (ja) 筋肉増量用組成物
CN111040044A (zh) 一种蛹虫草胞内多糖及制备方法及其在调节肠道菌群中的应用
JP2022140607A (ja) Ｌａｃｔｏｂａｃｉｌｌｕｓ ｆｅｒｍｅｎｔｕｍの新規株の組成物および使用の方法
JP5019961B2 (ja) インターロイキン１０産生促進剤
CN104771416B (zh) 用于控制体重的罗伊氏乳杆菌gmnl-263组合物及其用途
JP2018083761A (ja) 筋肉の分解抑制剤
WO2011108425A1 (fr) Méthode de préparation d'un immunomodulateur et immunomodulateur
KR101973514B1 (ko) 포도씨 분말을 포함하는 프리바이오틱스
KR20200046201A (ko) 비피도박테리움 애니멀리스 서브스페시스 락티스 HY8002와 비피도박테리움 아돌레센티스 HY8502의 유산균 조합을 이용한 진세노사이드 Rd가 강화된 발효홍삼 농축액을 유효성분으로 함유하는 알레르기성 비염을 개선하기 위한 조성물
KR101750948B1 (ko) 트라우스토키트리드계 변이균주 유래의 면역활성 증진 효과가 있는 세포외 다당류 및 이의 용도
KR102486043B1 (ko) 배추속 식물 또는 파속 식물 유래 세포밖 소포체를 유효성분으로 포함하는 염증성 질환의 예방, 개선 또는 치료용 조성물
KR102244732B1 (ko) 프로바이오틱 초산균인 아세토박터 파스테리아누스 mglv 및 이의 면역조절 효과
KR101894874B1 (ko) 스트렙토마이세스 프라질리스를 이용한 항염증 조성물
JP6016326B2 (ja) 乳酸菌のスクリーニング方法
KR102098914B1 (ko) 낫토 및 캐피어 발효물을 포함하는 항염증 또는 항산화 조성물
JP4689060B2 (ja) 免疫賦活組成物
JP6739155B2 (ja) 抗体産生調節剤
JP6480090B1 (ja) 二本鎖ｒｎａ高含有乳酸菌の製造方法及び該乳酸菌
JP7335012B1 (ja) 発現促進用組成物
US10314916B2 (en) Carrier for delivery of substance to phagocytes
JP6836298B1 (ja) 乳酸菌及び納豆菌を含む組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11750535

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11750535

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP